1-substituted-2-alkyl-3-(2-dialkylaminoethyl)indoles



United States Patent 3,478,054 1-SUBSTITUTED-2-ALKYL-3-(2-DIALKYLAMINO- ETHYL)INDOLES Thomas W. Pattison, King of Prussia, and David R.

Herbst, Wayne, Pa., assignors to American Home Products Corporation, New York, N.Y., a corporation of Delaware No Drawing. Filed Feb. 20, 1967, Ser. No. 617,079 Int. Cl. C07d 27/56 US. Cl. 260-32612 13 Claims ABSTRACT OF THE DISCLOSURE I-alkanoyl-, cycloalkylcarbonyl-, aralkyland arylsulfonyl derivatives (I) of 2-alkyl-3-[(2-dialkylamin0) ethylJindloes (II) are prepared by treating said indoles first with an alkali metal hydride or amide, then with an alkanoyl-, cycloalkylcarbonyl-, aralkylor arylsulfonyl halide. Compounds (1) have antibacterial, anti-inflammatory and hypotensive activity.

This invention relates to new and useful indole compounds. More particularly, it is concerned with l-substituted-Z alkyl 3-(Z-dialkylaminoethyl)indoles having valuable biological properties, being especially useful as antibacterials, anti-infiammatories and hypotensives.

It is, accordingly, a principal object to provide compounds effective to treat bacterial infections, inflammatory conditions and for the relief of hypertension, which are particularly effective, have low toxicity, lower central nervous system activity and which are characterized by high levels of activity for extended periods of time.

DESCRIPTION OF THE INVENTION The compounds contemplated by this invention are those of Formula I:

I Ll

ice

ethyl-2-methylindole, especially the hydrochloride; 3-(2- diethylamino)ethyl l-(p-fluorobenzyl)-2methylindole, especially the hydrochloride; 1 cyclohexycarbonyl 2- ethyl 3-[(2 diethylamino)ethyl]indole, especially the maleate; l-cyclopropylcarbonyl-Ii- (Z-diethylamino ethyl- 2-isopropylindole, especially the maleate', and 3-(2-diethylamino)ethyl Z-isopropyl-1-(p-methylbenzyl)indole, especially the maleate.

When used herein and in the appended claims the term (lower)alkyl contemplates straight or branched hydrocarbon chains of from about 1 to about 6 carbon atoms, illustrative members of which are methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, n-hexyl, 2-methy1pentyl, and the like. The term (l0wer) alkanoyl contemplates alkanoyl groups containing from about 2 to about 6 carbon atoms in straight or branched chain arrangements, illustrative members of which are acetyl, n-propionyl, n-butyroyl, i-butyroyl, n-pentanoyl, n-hexanoyl, Z-methylpentanoyl, and the like. The term (lower)alkoxy contemplates alkoxy groups containing from about 1 to about 6 carbon atoms in straight or branched chain arrangements, illustrative members of which are methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy, n-pentoxy, n-hexyloxy, 2- methylpentoxy, and the like. The term halo includes chlorine, bromine, fluorine and iodine.

The new compounds of this invention are prepared by first treating a suspension of a selected indole of Formula II.

wherein R and R are as defined hereinabove, in an inert solvent, such as a di(lower)alkylamide, e.g., dimethylformamide or an aromatic hydrocarbon, e.g., toluene, with a hydrogen-displacement agent, such as an alkali metal hydride or amide, preferably sodium hydride, at a temperature of from about 25 C. to about C. for a period of from about 1 to about 4 hours. Thereafter, an aralkyl, alkanoyl, cycloalkylcarbonyl, or arylsulfonyl halide is added to the reaction mixture at a temperature of from about 25 C. to about 100 C. and allowed to react for from about 16- to about 24 hours, preferably for about 20 hours. Distillation of the solvent, solution of the residue in benzene, washing with dilute aqueous potassium bicarbonate solution, then with water, drying and evaporation of the solvent, provide the crude base which can be chromatographically purified on an alumina column.

The l-alkanoyl, cycloalkylcarbonyl, aralkyl or arylsulfonyl free base derivatives of Formula I obtained by the foregoing sequence are convertible into their acid addition salts, such as the hydrogen chloride addition salt, by treating an etheral solution of the free base with either gaseous or isopropanolic hydrogen chloride. Other acid salts may also be prepared by treating the free base form of the compounds described with other organic or inorganic acids. Acids suitable for this purpose are hydrobromic, sulfuric, phosphoric, nitric, benzoic, methanesulfonic, p-toluenesulfonic, benzenesulfonic, naphthalenesulfonic, salicylic, glycolic, acetic, maleic, succinic, tartaric, stearic, palmitic, citric, glutaric, lactic, pamoic and the like.

Intermediates for indoles of Formula II, used as starting materials are known or are prepared from N-acyl-otoluidines by methods described in detail in, for example, F. Piozzi and M. Langella, Gazz. Chem. Ital., 93, 1382 (1963) and C. Cardani, F. Piozzi and G. Casnati, ibid. 85, 263 (1955). Then, employing the procedure of M. E. Spector and W. C. Anthony, US. 2,870,162, the intermediates are converted via the amides into the requisite compounds of Formula II.

Compounds of Formula I herein are valuable pharmaceutical agents. In particular, the new compounds possess antibacterial, anti-inflammatory and hypotensive activity. This makes them useful to treat diseases in warm-blooded animals which are commonly alleviated with such agents.

When used for the purposes described above, it may be desirable according to conventional pharmaceutical practice to combine the specific compound selected into compositions suitable for enteral or parenteral administration by combining the same with a pharmaceutically acceptable organic or inorganic carrier. The composition may be prepared in solid form, such as tablets or in liquid form such as a solution, suspension or emulsion. Suitable liquid carriers include water, gelatin, lactose, starch, talc, vegetable oils, alcohols, polyalcohols, gums, U.S.P. syrups and the like. The pharmaceutical composition in addition to the active principle and the carrier may include auxiliary materials such as coloring, stabilizing, wetting or emulsifying agents. It is of course recognized as essential that the carrier as Well as any other materials present with the active principle be inert with respect thereto.

The dosage of the present therapeutic agents will vary with the form of administration and the particular compound selected. Furthermore, it will vary with the particular subject being treated. Generally, treatment is initiated with small dosages, substantially less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under the circumstances is reached. It will generally be found that when the composition is administered orally, larger quantities of the active agent will be required to produce the same effect as a smaller quantity given parenterally. In general, the compounds of this invention are most desirably administered at a concentration level that will afford effective results Without causing any harmful side effects and preferably at a level that is in the range of from about 10 mg. to about 400 mg. per day in a 70 kg. animal, although as aforementioned, variations will occur. However, a dosage level that is in the range of from about 20 mg. to about 200 mg. per day in a 70 kg. animal is desirably employed to achieve most effective results.

DESCRIPTION OF THE PREFERRED EMBODIMENTS TABLE I Compound Name of Base XIV 2-methyl-3-(Z-dimethylamino)ethyl-1-(phenylsulfonyb- XV 2-rlrl eizgil-3-(2-dimethylamin0)ethyl-1-(p-tolylsulfonyD- XVI 1-(pmethoxyphenylsulfonyl-Z-methyl-3-[(Z-dimethylamino)ethyl]indle.

Compound Name of Base XVII 1-(3,4-dichlorophenylsulfonyl) -2-methyl-3-[ (Z-dimethylamino)ethyl]indole. XVIII 1-benzyl-2-methyl-3-[ (2-dirnethylammo) ethylhndole. XIX l-(p-chlorobenzyl)-2-methyl-3-[(2-d1methylam1no)- ethyl]indole. XX 2-me21th1y1-3-(2-din1ethylamino)ethyl-1-(p-methylbenzyD- in o e. XXL 2-methyl-3-(2-dimethylamino)ethyl-l-(p-methoxybenzylfindole. XXII l-cyclopropylcarbonyl-2-methyl3-[(2-dmiethylammo)- ethyl]indole. XXIII l-cyclopentylcarbonyl-2-methyl-3-[(2-dimethylam1no)- ethylllndole. XXIV-. 1-cycl0hexylcarhonyl-Z-methyl-B-I(2-dunethylamlno)- ethyl]indole. XXV 2-methyl-3-(2-dimethylamino) ethyl-1-(4-methylvalery1)- indole. XXVI 3-(2-(t1iiethylamino)ethyl-Z-methyl-l-(phenylsulfonyl)- in ole. XXVII 1-(p-chlorophenylsulfonyl) 3- (Z-diethylamino) ethyl-2- methylindole. XXVIII 3-(231mmylamino)ethyl-2-methyl-1-(p-tolylsulfonyl)- in o e. XXIX 3-(2-diethylamino)ethyl-1-(p-methoxyphenylsulfonyl)- 2-methylind0le. XXX 1-(3,4-dichlorophenylsulfonyl)-3-(2-d1ethylam1no) ethyl- Z-methylindole. XXXI 1-benzoyl-3-(Z-diethylamino) ethyl-2-methyl1ndole. XXXII 1-(pzhlorobenzyl-3-(2-diethylamino)ethyl-Z-methylin ole. XXXIII. 3-(2-(cilicfthylamlno) ethylQ-methyl-l-(p-methylbenzyl) in o e. XXXIV 3-(2-diethylamino)ethyl-I-(p-methoxybenzyl)-2-methylindole. XXXV 3-(2-diethylamino)ethyl-l-(p-fluorobenzyl)-2-methylindo e. XXXVI 1-cyclopropylcarbonyl-3-(Z-diethylamino) ethyl-2- methylindole. XXXVIL. 1-cyclopentylcarbonyl-3-(Z-diethylammo) ethyl-2- methylindole. XXXVIII l-cyclohexylcarbonyl-3-(2-diethylammo)ethyl-2- methylindole. XXXIX- 3- (2-diethylamino) ethyl-2-Inethyl-I- (4-methylvaleryl) indo e. XL 1-(p-chlorobenzyl)-2-methyl-3-[(2-dipropylamino)- ethyl]indole. XLI Z methyI-I-(p-methy1benzyl)-3-[(2-dipropy1am1no) ethyflindole. XLII l-cyclopropylcarbonyl-2-methyl-3-[(2-d1propylam1no)- ethyl]indole. XLIII 2-rneath1y1-3-(2-dipropylamino) ethyl-l-(p-tolylsulfonyD- in o e. XLIV Z-methyl-l-(-methylvaleryl)-3-[(2-dipropylarnino)- ethyl]indole. XLV l-cyclohexylcarb0nyl-2-ethyl-3-[(2-diethylamino)- ethyl]indole. XLVI 2-etliiyll-3-(2-diethylamino)ethyl-1-( l-methylvaleryl)- m o e. XLVII Z-ethiylI-S-(2-diethylamino) ethyl-1-(phenylsulfonybm o e. 1-(pzl'ilorobenzyl)-2-ethyl-3-[(Z-diethylamino)ethyl]- m 0 e. XLIX l-cyclopropylcarb onyl-3-(2-diethylamino) ethyl-2- isopropylindole. L 3-(2-lcilitlsthylamino)ethyl-2-isopropy1-l-(-methylvaleryl)- m o e. LI 3-( 2-litfthylamin0) ethyl-Z-isopropyl-l-(p-methylbenzyl)- m o e.

Example 1.3- (Z-diethyI-amino ethyl-2-methyl-l- (phenylsulfonyl)indole A solution of 8.07 g. 3-(2-diethylamino)ethyI-Z-methyl indole in 200 ml. dry dimethylformamide (DMF) is stirred with 2.02 g. of about 50% sodium hydride-mineral oil dispersion for one hour at about 25 C., then 7.43 g. of benzene sulfonyl chloride in 30 ml. DMF is added dropwise with cooling (ice-water bath). When the addition is complete, the reaction mixture is stirred at about 25 C. for 18 hours and then is freed of solvent. The residue is dissolved in benzene, washed successively with dilute, aqueous potassium bicarbonate solution, Water, dried (sodium sulfate) and the solvent is distilled. After solution in a minimum amount of benzene, the residue is chromatographically purified on a 250 g. column of neutral, activity III alumina. Elution with benzene-hexane combinations (1:9 to 1:1) affords a base which is dissolved in dry ether and treated with excess isopropanolic hydrogen chloride. The resulting salt is crystallized from acetone-ethyl acetate to provide the product as the hydrochloride (XXVI, 19%), M.P. 180-182 C.,

i 4.22, 7.34, 8.4.7 EtOH 252-262 14,100 m,.

max.

TABLE II U.V. LR"

Table 1 Crystallizing A555. EtOH, Product Reactant solvent 1 M.P., 0. (m e10" Xxvn. 01 30201 A-O, A-B 153-170 4.22, 7.35, 3.49 252-250 154.0

XXVIII 5145 30501 A-B 173-175 4.25, 7.35, 3.51 250-253 133.0

XXIX p 1530 30501 A 1435151.0--{ 254 210.0

xxx 34012 30201 A-B 173-179 4.27, 7.39, 3.49 254-250 153.3

XXXI 011501 4-13---- 143-145 3.91, 4.07 Z3332 277-233 79.3 xxx1r 01 011201- B- 143445 4.23, 4.37 233-239 33.5 292-295 75.9

275281 71. 5 2515mm... 1113 0315131 A-B 145-147 4.15 235. 5 73.0 291-295 71.5

XXxrv p-MeOOH2Cl B 135-137 4. 17 g 274-231 55.0 xxXv 1 011501 B 1375-1400.-. 3.99, 4.25 232239 53.3 294 55.0

251-255 155.0 xxxvr--- c001 A 155-153 4.13, 5.92 233-239 52.3 303 55.9

I 243-254 141.0 XXXVII B 3'95! l 251. 5 151.0 XXXVIIL. @0001"... A 187 139 290-305 49.0

xxxnn--- (Me)2CH(CH2)2COC1 B 127-123 4.15, 4.22, 5.37 3%, gg-g XVIII mm -3.- 214-215 4.00, 4.15 332 1 1 A =Acetone; B Ethyl acetate; 0 Hexane.

1 Halo compound in DMF is added dropwise to the sodium salt-DMF solution at C. and the mixture is stirred at 55 C. for 18 hours.

Example 2.-1-cyclopropylcarbony1-2-methyl-3- Z-dimethylamino) ethyl] indole To 8.09 g. 2-methyl-3-[(2-dimethylamino)ethyl]indole 40 stirring continued at about 25 C. for 16 hours. After removal of the solvent, the residue is dissolved in benzene, washed with dilute aqueous potassium bicarbonate solution, water, dried (sodium sulfate) and the solvent evaporated. Solution of the oil in a minimum amount of benzene and purification on a 300 g. column of neutral activity III alumina aifords, from the 1:1 benzene-hexane elhates, an oil which is dissolved in dry ether and treated with isopropanolic hydrogen chloride. Two recrystallizations (isopropanol) of the salt thus formed yields 1- cyclopropylcarbonyl 2 methyl 3-[(2-dimethylamino) ethy1]indole hydrochloride (XXII, yield 34% dec. 244- 246 C.

REE; 3.92, 4.10, 5.91 1, A1 1; EtOH 249.5 (6 16,450), 300 (5,980) my The derivatives in Table III are prepared by the same process employing the appropriate indole and the reactant shown. In two instances (XIV and XVIII) the products are characterized as the free bases.

TABLE 111 Table I Recrystallizing 152;; .1 5 11, Product Reaetant solvent 1 M.P., C. 4 (mp) 510' XIV s02o1 7. 37, 3. 253.5 133.0 XV 1155 30501 7.33, 3. 54 251-259 134. 3 XVI p-MeOSO2C1 g3, 253 208. 0 XVII 3,4 015 30501 o 3332 3. 53, 7127131 51 250 140.5 01 011501 A 21452170 0. 3. 93, 4. 13 231 sh 59.9 287 73.6 294.5 sh 57. 5 275 sh 63. 0 XX 0151513: A 194-195 3 92,411 233 70.9 292-296 67. 0 273-235 34.1 xxn- 11450 011201 A 193-199 3 93, 4. 03 235. 5 33. 5 293-295 70.9

243-254 149. 7 XXIII -coo1 :o 237-239 3. 93, 4. 12, 5. 39 290-304 45.3

3. 91, 3. 97, 249. 5 153. 0 XXIV 0001 A-E 235-237 4. 07, 5. 39 235-301 51. 5

XXV (mncmcmnoom 14 225-225 3.93, 5.37, 4 10 245 153. 3 237-302 50. 5

1 A =Aeetone; B Ethyl acetate; 0 =Hexane; D =Isopropanol; E Diohloromethane.

1 Free base.

7 Example 3.2-ethyl-3-(Z-diethylaminoethyl)-1- (4-methylvaleryl)indole Sodium hydride (1.58 g., about 50% mineral oil dispersion), 7.33 g. of 2-ethyl-3-[(2-diethylamino)ethylj indole and 200 ml. dry DMF are stirred at 4045 C. for 3 hours, 4.44 g. 4-methylvaleryl chloride is added dropwise and the mixture is maintained at 45 C. for 18 hours. The solvent is removed and the residue, dissolved in benzene, is washed with dilute aqueous potassium 3- Z-diethylaminoethyl 1- (m-iodobenzyl) -2-tbutylindole;

lp-bromophenylsulfonyl) -3 (Z-diethylamino ethyl] Z-methylindole;

3-(2-diethylaminoethyl)-1-(p-iodophenylpher1ylsulfonyl)-2-methylindole; and

1- 2,5 -dibromophenylsulfonyl) -3-[ (Z-di-n-hexylamino) ethyl] -2-methylindole.

We claim:

bicarbonate solution, water and dried (sodium sulfate). 10 A Compound Selectfid from those 0f formula! Distillation of the solvent provides a crude base which is dissolved in a minimal quantity of benzene and is chromatographically purified On a 300 g. column of neutral, activity III alumina. The purified base isolated If A from the hexane and benzene-hexane (1:9) eluates is d R3 dissolved in dry ether and treated with an equimolar 2 quantity of maleic acid in anhydrous ether. Two recrystallizations (isopropanol-ether) of the salt so formed Wherem: R1 dluower) alkylammo; R2 13 (lower) yield 2 ethyl 3 (2 diethylaminoethyl) 1 (4 methy1 2 alkanoyl, cycloalkylcarbonyl of from 4 to 7 carbon atoms, valeryl) indole maleate (XLVI, 19%), dec. 84-85 c. g y L o y a u w o w g n. r o a o enzy p eny su fony ower -a y p eny su ony f g g-gg gg 3gg (6 0 (lower)-alkoxyphenyl-sulfonyl, halophenylsulfonyl or dihalophenylsulfonyl; and R is (lower) alkyl, and pharmap y the pp p ole and the l1sted receutically acceptable acid addition salts thereof. actant, the compounds of Table IV are Obtalned 1n a 25 2, A compound as defi d in claim 1 which is 1 1 slmrlar manner. In two lnstances (XLI and XLII) the propylcarbonyl Z-methyl 3-[(2-dimethylamino)ethy1] hydrochloride salts are prepared rather than the maleates. indole.

TABLE IV I U.V. T bl I o t 11' A K r Pi odi ict Reactant so l viri t 112mg M.P., C. m e10 XLV @0001 A-B- 114-116 4.08, 5.85, 250 156.0 6. 17, a. 36 290-303 48. a

4.25, 5. 89, XLVII- qSSOzCl A43- 105-106 6. 18, 6. 35, 257. 5 138. 5

410 .8", xLvrrr p-C1OH2G1 A-B- 127-128 0. 121 6.2 z zi 33.9 290.5 74.9

3.87, 7, XLIX COC1 AB 67-69 dec 6.1?51. 291-383 6.35

i 4. 17, 5. s4, 14 L (M8)2CH(CH2)2COCI AB- 122-124 6. 17, 6.3 272 5 102.8 292-302 40.6

LI p-MeCH2Bl' A-B 147-149 4. 10, 5.87, 285 82.6 6. 17, 6. 3 292 78. 1

X D- 2 91-92 285 no XLI 2 p-Me sCHzBr o mews 4.17{ 1 3; 250 161.0 XLII cool 0 148150 415,505{ 302 60.5

4. 2s, 5. 90, XLIII p-MeqbSOzCH A-B- 112-114 15.17.4130,} 255 136.0

3. 90, 5.89, 242 169. 5 XLIV- (lVIe)2CH(CH2)2COCl A-B 118-120 6. 19, 6. 33 275 sh 88.6 287-303 49.1

1 A=Isopropanol; B =Diethyl ether, C=ethy1 acetate. 2 Hydrochloride salt.

Example 4 1- (p-butoxybenzyl) -3-[2-(diethylamino)ethyl] -2- ethylindole;

1-(p-bromobenzyl-3-)Z-diethylaminoethyl-Z-nhexylindole;

3. A compound as defined in claim 2 in the form of an acid addition salt with hydrogen chloride.

4. A compound as defined in claim 1, which is l-cyclopentylcarbonyl 2 methyl-3-[(2-dimethylamino)ethyl] indole.

5. A compound as defined in claim 4 in the form of an acid addition salt with hydrogen chloride.

6. A compound as defined in claim 1, which is l-(3,4- dichlorophenylsulfonyl) 3 (2 diethylamino)-ethyl-2- methylindole.

7. A compound as defined in claim 6 in the form of an acid addition salt with hydrogen chloride.

8. A compound as defined in claim 1, which is l-cyclohexylcarbonyl-2-ethyl-3-[ (Z-diethylamino) ethyl] indole.

9. A compound as defined in claim 8 in the form of an acid addition salt with maleic acid.

10. A compound as defined in claim 1, which is 1- cyclopropylcarbonyl 3-(2 diethylamino)ethyl 2-isopropylindole.

11. A compound as defined in claim 10 in the form of an acid addition salt with maleic acid.

12. 3 (Z-diethylamino)-ethyl-2-isopropy1-1-(p-methylbenzyl) indole.

13. A compound as defined in claim 12 in the form of an acid addition salt with maleic acid.

References Cited Ehrhart et al.: Chem. Abs., vol. 56, 440i, a'bst. of Arch. Pharm. 294-550-5 (1961).

Thesing et al.: Chem. Abs., vol. 62-l0398h. abst. of Ann. Chem. 680-52-9 (1964).

ALEX MAZEL, Primary Examiner I. A. NARCAVAGE, Assistant Examiner US. Cl. X.R. 

